Finding the right chemistry

Ramipril is a lifesaver for many people. It lowers blood pressure and reduces the risk of heart attacks and strokes. The production of such drugs is a sensitive process. The slightest deviation in product quality can have disastrous consequences for those who depend on them. Bilfinger Berger Industrial Services supports pharmaceutical industry giant Sanofi-Aventis in the production of this coveted active ingredient.

The substance bearing the name Ramipril is a real star—one only catches glimpses of it from a distance. It is a white powder trickling through a funnel into a drum behind panes of glass which protect the clean room. Within the clean room, the substance has traversed three stories of the factory building, passing through kilometers of tubes, over a hundred vessels, three centrifuges, two dryers, two solvent treatment plants and countless pumps, at temperatures between 0 and 100 degrees Celsius and under high pressure. A fully automated process which involves ten stages of chemical synthesis.

The producer of the substance, Sanofi-Aventis, is understandably reluctant to reveal any further details of how Ramipril is produced. It is, after all, the vital ingredient in top-selling medications, the success of which has earned them the title of “blockbusters”: last year alone, Ramipril preparations generated sales in excess of a billion euro for drug maker Sanofi-Aventis.

Sensitive production
This success reflects a health problem affecting people all over the world: almost six percent of all deaths are attributable to high blood pressure. Ramipril intervenes in the complex system of messenger substances that control heart function and blood pressure. One of these messengers is the hormone angiotensin, which constricts blood vessels and thereby increases blood pressure. Ramipril inhibits the body’s own enzyme which is involved in the production of this hormone. As a result, less angiotensin is produced, the blood vessels expand and the heart is no longer forced to pump against such high resistance. The risk of heart attacks and strokes is reduced.

Sanofi-Aventis manufactures this substance in Frankfurt, in the Industriepark Höchst, right next door to Bilfinger Berger Industrial Services. Bilfinger Berger helps to maintain the production equipment used by a number of companies in the Industriepark, including the Ramipril plant D712 operated by Sanofi-Aventis. One man who knows his way around here is Wolfgang Seeling. A quick glance at the worn folder on his desk is proof of that. It lists the orders received in recent years for the D712 plant—well over a hundred of them. Seeling was there just the day before to reset the zero point of the level indicator that shows the contents of one of the containers. Level indicators and pressure gauges— these are his specialty. He knows, for example, how to tune a level indicator to prevent disturbance by an agitator inside the vessel which would otherwise cause it to show an incorrect reading. “We call it tuning out parasitic echoes,” explains Seeling.

There are some sectors in which a liter either way does not matter—or a kilo or a few degrees Celsius. But the pharmaceutical industry tolerates no deviations of measurement. Least of all in the production of highly sensitive ingredients, where even the slightest variance can have a negative impact on patients.

Ask Wolfgang Seeling why Sanofi-Aventis, the world’s third-largest drug company, does not itself install, calibrate and service such sensitive equipment, and he goes to a cupboard containing two dozen pressure gauges. Then he produces page after page of instructions detailing how to commission each individual type and asks rhetorically: “Why should Sanofi-Aventis concern itself with such a specialized field? Their business is researching drugs.”

Just how engineering-oriented the maintenance business can actually be becomes clearer just a few doors away from Wolfgang Seeling’s office, in the Bilfinger Berger Industrial Services testing laboratory. This is Helge Essig’s workplace. On behalf of Sanofi-Aventis he tests the accuracy of temperature sensors that can simply be clamped onto the outside of tubes rather than being screwed into the pipe itself. This makes it easier to keep the tube sterile. The laboratory has now developed into a kind of watchdog for measuring equipment. It is not just plant operators such as Sanofi-Aventis that have their gauges tested here—even the manufacturers use the laboratory’s services.

Bilfinger Berger has shared responsibility for the measuring equipment at the Ramipril plant ever since D712 was redeveloped a few years ago. The equipment that is now used to measure the material concentrations in containers and pipelines was designed by Bilfinger Berger Industrial Services. These devices automatically monitor changes in mixture concentration, a technique which is faster and more cost-effective than taking samples for laboratory analysis. The same team which conceived and installed the analytical system has since maintained the measuring points. This is one of the company’s particular strengths, says Manfred Sturm, one of the engineering specialists at Bilfinger Berger Industrial Services: “We stay on the ball throughout the entire life cycle of the production plant.”

High standards, utmost precision
The range of services provided by Industrial Services at the Industriepark Höchst also includes tasks such as scaffolding and staging, insulation and corrosionproofing. But even where it would be least expected at first glance, extreme precision is called for. Dirk-Harald Bestehorn paces through a workshop in the Machinery and Drive Systems section: lying on the floor at one end is a pallet containing dozens of pumps, electric motors, valves, condensers and gearboxes. Many are rusty, scratched and soiled. Some are the property of customers, others number among the pool of 12,000 units rented out by Bilfinger Berger Industrial Services. Here in this workshop the units will be completely dismantled, cleaned, serviced, repaired, fitted with new parts, reassembled, given a coat of paint and bench-tested. “When they leave here they’re like a new piece of machinery,” Bestehorn confirms. Every individual stage is also meticulously recorded. “If it isn’t written down, we didn’t do it,” he adds. Back in his office the mechanical engineer produces a micronizer for the Ramipril plant and demonstrates how inspecting a single piece of equipment can fill an entire file: Every component which comes into contact with the product requires a declaration confirming it is safe to use; every lubricant used, every cleaning agent, even the tiniest gasket must be approved; whole reports are on file confirming that certain surfaces are devoid of scratches which might harbor bacteria: “The standards in the pharmaceutical industry are the highest you could ever imagine.”

“Superb interplay”
If it were not already clear, one look at this folder is enough to make it obvious that the extreme complexity and sensitivity inherent in the manufacture of a substance such as Ramipril are best accommodated by a division of labor between specialist partners. “Manufacturing an ingredient such as this is a superb example of the interplay between engineering and chemistry,” enthuses Dr. Werner Sievers, production manager at D712.

The Industriepark Höchst provides the ideal conditions for Sanofi-Aventis and Bilfinger Berger Industrial Services to work together. Created originally as a result of the spin-off of individual activities from Hoechst AG to a variety of independent companies, the Park today is home to more than 80 businesses, from large multinationals to creative services providers. Together they represent an extraordinaryly dynamic force, says Dr. Joachim Kreysing of Bilfinger Berger Industrial Services: “Each year around € 350 million is invested in the Industriepark—that’s even more than in the heyday of Hoechst AG.”

(Text: Stefan Scheytt, Photos: Barbara Breyer)
Photographer Barbara Breyer, 43, admires the aesthetic aspect of machines—and the people who tend and understand them. Author Stefan Scheytt, 44, specializes in complex industrial and economic subjects. His reports can be found in publications including the “Neue Zürcher Zeitung”.